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Although different polymers can be used to produce polymeric NPs, depending on the
final aim and the loaded drug, all NPs have to present a certain set of characteristics [153].
These include biocompatibility, mechanical strength, degradability that follows the fit ki-
netics for the desirable aim, solubility, adequate shelf life, and approved by the regulatory
agencies (FDA and EMA, e.g.,) for use as constituents of drug delivery systems [153]. The
most commonly used polymers can be categorized as natural polymers, e.g., gelatin, albu-
min, chitosan, and sodium alginate; and synthetic, e.g., polylactides (PLA), poly (lactide
co-glycolides) (PLGA), polyethylene glycol (PEG), polyglycolides (PGA), polycaprolacton e
(PCL), poly (malic acid) (PMLA), polyorthoesters (POE), poly (methyl methacrylate)
(PMMA), polyacrylamide (PAM), poly (N-vinyl pyrrolidone) (PVP), etc. [104,129,154]. Den-
drimers are composed of a molecular core with repetitive and well-organized hyperbranched
polymers, with inner layers and exter nal functionalized-terminals [155,156]. These systems
offer favorable properties in comparison to normal polymers, such as presenting high water
solubility, polyvalency, and ability to easily penetrate cell walls and overcome biological bar-
riers [152,155,156]. The end groups at the external terminals determine some of the den-
drimers’ properties, i.e., solubility [157]. Some polymers used to synthesize dendrimers for
therapeutic purposes include polyamidoamine (PAMAM), poly (propylene imine) (PPI),
poly-
L-lysine, melamine, poly (etherhydroxylamine) (PEHMAN), poly (esteramine) (PEA),
PEG, and polyglycerol [156,157].
Polymeric NPs are also able to deliver the drug by disassembly upon stimuli at the target
site, and this is known as smart drug delivery [158]. Differe nt stimuli can trigger smart drug
delivery of polymeric NPs, including external stimuli (i.e., magnetic fields, changes in tem-
perature, irradiation with near-infrared or UV-vis radiation, ultrasound vibrations) and inter-
nal stimuli, that result from changes at the target site microenvironment (i.e., pH, oxidative or
reductive conditions, enzymatic alterations, ionic strength) [158,159]. Smart drug delivery us-
ing pH-sensitive polymeric NPs are of particular interest in inflammatory disorders and can-
cer, as the associated microenvironments have an intrinsically slightly acidic pH (<6.5),
compared to healthy tissues (pH ¼ 7.4). This specific condition causes the disassembly of
pH-sensitive polymeric NPs, with subsequent release of the associated content, at the target
site [159]. These stimuli-sensitivity properties of smart polymeric NPs depend on stimuli-
responsive elements or monomers copolymerized into the polymeric backbone [153,160].
In dendrimers, similar to smart polymeric NPs, drugs are conjugated through different types
of linkers (i.e., amides, esters, and hydrazones) that will cleave upon activation by previously
mentioned external stimuli [157].
The usefulness of polymeric NPs for the delivery of plant actives is demonstrated by
Opaxio, a commercialized a-poly-
L-glutamic acid-bound paclitaxel formulation through an
ester linkage, and Abraxane, a commercialized human albuminebound paclitaxel
[161,162]. In triple negative breast cancer, when compared to Taxol, Abraxane has a higher
response rate, significantly increasing complete response for this malignancy [ 163]. Opaxio
had been approved for the management of glioblastoma but withdrew phase III clinical trials
for ovarian and non-small cell lung cancers due to lack of improvement in survival outcomes
[164,165]. Opaxio improves paclitaxel’s water solubility and allows for prolonged and
passively targeted drug delivery, reducing side effects, and improving paclitaxel’s tumor
accumulation [165].
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Table 3.4 depicts examples of polymeric NPs formulations of plant actives/derivatives un-
der clinical trials.
5.2 Lipid-based nanoparticles
These nanosystems represent a vastly investigated class of nanosystems, with numerous
products already in clinical use or undergoing clinical trials (Table 3.5). There is a high diver-
sity of lipid-based nanosystems, including liposomes, SLNs, nanostructured lipid carriers
(NLCs), lipid nanocapsules, lipid-based micelles, transfersomes, ethosomes, and phytosomes.
In general, these carriers display low toxicity, are suitable for large-scale production, and are
cost-effective [96,98, 166,167]. Other advantageous properties include adequate loading capac-
ity, ability to promote a controlled drug release, biodegradable components, modulation of
biodistribution profile, suitability for different administration routes, and possibility of sur-
face modification with targeting ligands [96,98,166e168].
5.2.1 Liposomes
Among these lipid-based delivery systems, liposomes are undoubtedly the most well-
known and successful ones owing to their unique and versatile properties. Liposomes are
composed of one or more lipid bilayers divided by aqueous compartments, being majorly
constituted by phospholipids [168,169]. The clinical success of liposomes, demonstrated by
numerous approved formulations, can be attributed to their particular biocompatibility
and biodegradability of their main constituents, low toxicity, and the ability to incorporate
both hydrophilic and hydrophobic compounds [168e173]. Furthermore, these nanocarriers
improve the solubility and stability of associated molecules, avoid premature drug degrada-
tion, alter the biodistribution profile of molecules, and promo te a preferential accu mulation at
tumor or inflammation sites via the EPR effect. For instance, myricetin, a flavonoid
commonly found in vegetables, fruits, nuts, and herbs, displays relevant biological activity;
however, its poor solubility limits its applications. Therefore, researchers developed lipo-
somes loading this plant-derived compound as a strategy against glioblastoma, showing
improved solubility and anticancer effect via SIRT3-mediated glycolytic metabolism [174].
Specific ligands may be attached to liposomes surface, increasing selectivity toward the ac-
tion site, ultimately improving the therapeutic index [169,171,175]. A commonly used target-
ing moiety is folic acid, since the folate receptor is upregulated in different human cancers
[176]. Vincristine-loaded liposomes coated with this ligand were developed as a therapeutic
strategy against multidrug resistant cance r. The in vivo data showed that targeted liposomes
had a significant and dosage-dependent antitumor effect, compared to animals treated with
free vincristine [177]. Interestingly, dual-targeted liposomes (folic acid and transferrin)
loading doxorubicin significantly enhanced cell associati on in human cervical carcinoma
(HeLa), both in cell monolayers and in 3D spheroids [178]. Also, in a xenograft B-
lymphoma model, vincristine-loaded immunoliposomes targeting the CD20 epitope signifi-
cantly increased survival rates compared to nontargeted liposomes [179]. In another
approach, the iRGD peptide that targets a
v
-integrin receptors and neuropilin-1 was used
as specific ligand in liposomes loading paclitaxel conjugated with linoleic acid. In a murine
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TABLE 3.4 Polymeric nanoparticles for the delivery of plant bioactives/derivatives: applications and clinical
trials.
Commercial
name
Plant
Bioactive DDS Therapeutic applications
ClinicalTrials.org
ID Phase
OP-101 N-acetyl
cysteine
Dendrimer Adrenoleukodystrophy NCT04321980 1
Severe COVID-19 (reduction of
proinflammatory cytokines)
NCT04458298 2
NK105 Paclitaxel Polymeric
micelles
Metastatic/recurrent breast cancer NCT01644890 3
CRLX301 Docetaxel Polymer
conjugate
Advanced solid tumors NCT02380677 1/2a
NK012 Irinotecan
metabolite
(SN-38)
Polymeric
micelles
Advanced solid tumors and metastatic
colorectal cancer
NCT01238939 1
Advanced solid tumors and metastatic triple-
negative breast cancer
NCT01238952
Triple-negative breast cancer NCT00951054 2
Relapsed small cell lung cancer NCT00951613
Paclitaxel
micellar
Paclitaxel Epithelial ovarian, primary peritoneal, and
fallopian tube cancers
NCT00989131 3
BIND-014 Docetaxel Polymeric
NPs
Metastatic castration-resistant prostate cancer NCT01812746 2
Non-small cell lung cancer (second-line
treatment)
NCT01792479
KRAS positive or squamous cell non-small cell
lung cancer (second-line treatment)
NCT02283320
Urothelial carcinoma, cholangiocarcinoma,
cervical cancer, squamous cell carcinoma of the
head and neck
NCT02479178
Advanced or metastatic cancer NCT01300533 1
Docetaxel-
PNP
Advanced solid tumors NCT01103791
NCT02274610
Theracurmin Curcumin Schizophrenia (improvement of behavior,
cognition, and neuroplasticity)
NCT02104752 1 and
2
N/A Melaleuca
alternifolia oil
Bacterial infection (reduction of biofilm
formation in plaque-free and plaque-covered
teeth)
NCT02695901 4
CRLX101 Camptothecin Cyclodextrin-
PEG
conjugate
Metastatic castration-resistant prostate cancer
and prostate neoplasms
NCT03531827 2
N/A Moringa
oleifera leaf
Polymeric
NPs
Otomycosis (antifungal) NCT04768829 1
DDS, drug delivery system; NPs, nanoparticles; N/A, not applicable; PEG, polyethylene glycol.
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TABLE 3.5 Examples of lipid-based plant bioactives/derivatives in clinical trials.
Bioactive/
Derivative
Lipid-based
DDS Therapeutic applications
ClinicalTrials.gov
ID Phase
Doxorubicin Liposomes Kaposi sarcoma NCT02659930 1
Relapsed/refractory solid tumors in children NCT02536183 1
Locally advanced soft tissue sarcoma (neoadjuvant
treatment)
NCT04765228 2
Advanced or unresectable angiosarcoma NCT04859465 2
Platinum-partial sensitive recurrent ovarian cancer NCT04337632 3
Epithelial ovarian cancer NCT03794778 4
Irinotecan Liposomes Advanced biliary tract cancer NCT05009953 2
Extra-pulmonary neuroendocrine carcinoma NCT03837977 2
Paclitaxel Liposomes Stage IIIB/IIIC/IV NSCLC (first-line treatment) NCT03987867 1
Esophageal squamous cell carcinoma NCT03946969 1 and
2
Pediatric advanced nasopharyngeal carcinoma NCT03020329 2
Advanced pancreatic cancer NCT04217096 4
Topotecan Liposomes Advanced solid tumors NCT04047251 1
Vincristine Liposomes CD22-positive (þ) B-cell acute lymphoblastic
leukemia
NCT03851081 1 and
2
Daunorubicin Liposomes Acute myeloid leukemia NCT03672539 2
NCT02724163 3
NCT03988205 4
Amphotericin B Liposomes Cutaneous leishmaniasis (Leishmania major and tropica) NCT02656797 2
Mucosal leishmaniasis NCT04799236 3
Cryptococcal meningitis NCT03945448 2
Chronic pulmonary aspergillosis NCT03656081 3
Glutathione Liposomes Gulf war illness NCT02848417 1 and
2
Curcumin Liposomes Hepatic insulin resistance and NAFLD in overweight
or obese patients
NCT04315350 N/A
Safety and pharmacokinetics after oral intake NCT03530436 N/A
Resveratrol and
curcumin
Liposomes Amyotrophic lateral sclerosis NCT04654689 2
Paclitaxel Lipid
nanoparticles
Coronary artery disease, atherosclerosis, and
inflammation
NCT04148833 2 and
3
DDS, drug delivery system; N/A, not applicable; NAFLD, non-alcoholic fatty liver disease; NSCLC, non-small cell lung cancer.
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melanoma model, the biodistribution studies showed a higher accumulation of the com-
pound in the tumor, which was correlated with the superior therapeutic effect observed
for the targeted liposomes [180].
Taking advantage of endogenous (pH and enzymes) or exogenous (light, ultrasound, X-
ray, heat) stimuli, a triggered-content release from liposomes may be achieved [181]. For
example, research ers have coated liposomes with succinyl-chitosan for a pH-triggered release
of quercetin and resveratrol at the intestinal level (pH ¼ 7). This strategy increased the stabil-
ity of the nanosystem and successfully promoted the release of the polyphenols at the desired
pH [182]. In another approach, citraconic anhydride was used as the pH-responsive linker in
curcumin-loaded liposomes. These demonstrated a higher cytotoxic activity against MCF-7
cancer cells, compared to the non-pH-sensitive counterpart [183]. Recently, a functional poly-
meric lipid was synthetized to promote liposomal drug release through the action of
cathepsin B enzyme, a protease known to be overexpressed in different cancers. In vitro, these
enzyme-responsive liposomes, loading doxorubicin, exerted cytotoxic effects on HepG2 cells.
In a zebrafish (Danio rerio) model using the same cell line, tumor progression was impaired, in
comparison with animals treated with free doxorubicin [184].
The versatility of liposomes for topical applications is confirmed by the combination of
phospholipids with a single chain surfactant, such as Tween 80 that provides greater
flexibility to the lipid vesicles. Taking advantage of this feature, researchers developed
naringenin-loaded elastic liposomes and demonstrated an enhanced permeation and deposi-
tion of the flavanone in the skin, associated with reduced irritation [185]. More recently,
innovative exosomelike liposomes were develop ed as a tool to deliver curcumin against
Alzheimer disease. In vitro, these liposomes did not induce cytotoxic effects in
fibroblast and neuronal cells and displayed a neuroprotective activity. Furthermore, in zebra-
fish embryos, accumulation at the brain and yolk sac was observed, with no associated
toxicity [186].
Besides their usefulness in drug delivery, lipos omes are also being investigated as carriers
of imaging agents, acting as theranostic platforms [187 ]. Recently, magnetic resveratrol-
loaded liposomes were evaluated as a theranostic tool for brain targeting in a Parkinsons dis-
ease rat model. The results showed that the exposure to an external magnetic field greatly
improved the brain accumulation of resveratrol, which translated into an enhanced therapeu-
tic effect [ 188]. In another interesting work, plant chlorophyll derivatives, presenting intrinsic
fluorescence, were encapsulated in liposomes for imaging-guided photodynamic therapy. Li-
posomes successfully improved the compounds’ solubility, prolonged blood circulation
times, and changed the biodistribution profile. In 4T1 tumor mice models, liposomes signif-
icantly reduced tumor progression upon laser irradiation. Moreover, this nanoformulation
could be employed as contrast agent for tri-model imaging modalities: fluorescence, photo-
acoustic, and single-photon emission computed tomography (SPECT/CT) [189].
5.2.2 Solid lipid nanocarriers and nanostructured lipid carriers
SLNs consist in crystal solid lipid matrices stabilized by emulsifying agents, forming NPs
with median sizes in the range of 50e1000 nm [168,190,191]. These lipidic systems are able to
accommodate molecules between fatty acid chains, protecting the associated compounds
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from degradation and promoting a controlled drug release [166,192,193]. Despite their advan-
tages as nanocarriers, SLNs display some limitations, such as inadequate drug loading and
drug leakage during storage. To overcome these issues, NLCs were developed. These are
characterized by the replacement of a fraction of the solid lipid with an oil, resulting in a
less-ordered matrix [167,194,195].
Different SLNs and NLCs, with or without stimuli-responsive properties, have been
designed for several applications. For instance, considering CNS disorders, these carriers
have been employed for direct nose-to-brain delivery of compounds, avoiding the need to
cross the bloodebrain barrier. These lipid-based NPs adhere to the olfactory epithelium
and increase residence time within the nasal mucosa, thus enhancing the bioavailability of
drugs in the brain [196,197]. For instance, intranasal administration of SLNs loaded with ros-
marinic acid, a bioactive plant phenolic compound commonly found in herbs and other
plants (e.g., rosemary), was evaluated as a therapeutic approach toward Huntington disease.
The in vivo resu lts showed that, compared to the free compound, the body weight and loco-
motor and motor coordination of animals treated with SLNs improved. Importantly, the
intranasal administration route led to optimal drug concentration in the brain, opposed to
the intravenous route [198]. Plant-derived compounds may be used not only as bioactive
agents but also as targeting moieties. One example is given by the brain targeting of SLNs
loading pueraria flavones, isoflavonoids derived from Pueraria lobata or Pueraria thom sonii,
through the conjugation of borneol, a bicyclic monoterpene found in Dryobalanops aromatica
tree. Preclinical data in healthy rats demonstrated higher accumulation of targeted SLNs
compared to the nontargeted counterpart, strengthening the therapeutic potential of pueraria
flavones in the treatment of brain-related disorders [199]. Interestingly, natural compounds
may also act as cancer sensitizers and promote a synergistic action. In vitro data using
MDA-MBA231 breast cancer cells demonstrated that myricetin-loaded NLCs functioned as
sensitizing agents, improving the antitumor activity of docetaxel [200]. Moreover, in vitro
studies using MCF-7 breast cancer cells showed a synergistic effect between methotrexate
and lycopene [201]. This red carotenoid pigment, naturally present in tomatoes, watermelons,
pink grapefruits, and apricots, is poorly soluble and is sensitive to light, oxygen, and temper-
ature variations. Its association to SLNs allowed to improve chemical stability and solubility,
showing high cellular uptake and increased anticancer activity. Also, a dose- and time-
dependent synergism was observed when in combination with methotrexate [201].
Regarding stimuli-responsive systems, thermoresponsive SLNs have been investigated in
preclinical studies using Nu/Nu mice bearing MDA-MB-231 tumors [202]. These SLNs,
loading the clinically approved photosensitizer temoporfin (Foscan) within the enriched fatty
alcohol (1-tetradecanol) core, were designed for applications in phot odynamic therapy. The
therapeutic efficacy of this therapy is hindered by limited accumulation of photosensitizers
at target sites. The use of SLNs proved to be advantageous, greatly improving the anticancer
activity of temoporfin, compared with the commercially available formulation [202].
Both SLNs and NLCs may be advantageous for topical applications of plant actives (e.g.,
resveratrol) in cosmetics or for the treatment of autoimmune, inflammatory, and cancerous
skin diseases, since the retention of these NPs at the skin surface and the formation of an
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occlusive film is expected [203]. This, in turn, enhances drug release and promotes the hydra-
tion of the stratum corneum [204]. Research has shown that both carriers equally promote the
occlusive effect. However, NLCs promoted the permeation of the marker Nile red into the
stratum corneum in a higher extent, when compared to SLNs, indicating the importance of
particle physicochemical properties [205]. This was confirmed by a study using curcumin-
loaded SLNs and NLCs as wound healing approach. On one side, both NPs protected curcu-
min from photodegradation, a feature that was independent from matrix fluidity. On the
other side, NLCs improved wound healing, even when loading lower amounts of curcumin
[206]. Also related with wound treatment, the use of NLCs for the combined delivery of Lav-
andula x intermedia “Sumian” essential oil and ferulic acid [207 ], an abundant phenolic acid
commonly found in a variety of plant tissues [208], significantly promoted cell migration
[207]. Another research work highlighted key differences between SLNs and NLCs for topical
delivery of psoralen [209], a tricyclic furocoumarin found in Psoralea corylifolia and in other
plants and fruits [210]. Compared to SLNs, NLCs demonstrated a higher permeation and
enhanced controlled drug release, which was attributed, in part, to the smaller particle
size, reduced viscosity, and the presence of liquid lipids [209].
SLNs and NLCs are also suitable nanocarriers for parenteral administration of plant-
derived compounds, and the selection of the most appropriate one depends on their
composition and physicochemical properties. For example, in a work comparing NLCs
(with squalene as liquid matrix) and SLNs (with two different glycerides as core material:
Precirol [SLN-P] or Compritol [SLN-C]) as carriers of camptothecin, all were demonstrated
to be safe for parenteral administration, with SLN-P showing higher cytotoxic effects [211].
5.2.3 Lipid nanocapsules
Lipid nanocapsules (LNCs) are vesicles that mimic lipoproteins, being composed of a sur-
factant shell and a lipidic core. A size range of 20e100 nm may be obtained depending on the
different ratios of each component [212,213]. Furthermore, these nanocarriers may be func-
tionalized and can be administered via distinct routes, including intravenous [213], pulmo-
nary [214], and oral [213]. Authors have successfully designed and tested in vitro
paclitaxel-loaded LNCs in the form of an aerosol, being suitable for applications in future pre-
clinical and clinical investigations [214]. Several lipophilic essential oils have already been
formulated in these systems: eugenol, derived from clove, cinnamon, and pepper; carvacrol,
found in aromatic plants; and trans-cinnamaldehyde, present in species of the genus Cinna-
momum [212]. Using human breast cancer cells MCF-7, researchers demonstrated that LNCs,
with a polysorbate 80-coated poly-e-caprolactone shell, enhanced the cytotoxic activity of a
lycopene-rich extract from red guava (Psidium guajava L.) and did not induce hemolysis
[215]. In other studies, synergistic activity using LNCs was achieved against cancer [216]
and bacteria [212]. In a study focusing on hepatocellular carcinoma, LNCs were co-loaded
with quercetin and sorafenib, an approved targeted therapy. For dual targeting, a lactoferrin
shell was further coated with lactobionic acid, promoting the binding to lactoferrin receptors
and asialoglycoprotein receptors, respectively, which are overexpressed in hepatoma cells.
This dual-targeted nanosystem, together with drug combination, showed high uptake by
HepG2 cells and increased cytotoxicity. In a chemically induced murine model of hepatocel-
lular carcinoma, this approach greatly impaired tumor progression, as demonstrated by acti-
vation of caspase-3 and reduction of NF-kB, TNF-a, and VEGF-1 expression levels [216]. Also,
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a synergistic bactericidal action, against Gram-negative strains, was observed when
combining LNCs loading essential oils with doxycycline [212].
LNCs have also been investigated as theranostic tools, combining therapy and imaging
modalities. LNCs were functionalized with a cell-penetrating peptide (NFL-TBS.40-63) and
were co-loaded with paclitaxel and the far-red fluorochrome DiD for glioblastoma theranos-
tics. In vitro, cellular uptake was successfully achieved and, in vivo, these nanocarriers pref-
erentially accumulated at target sites and impaired tumor progression. The results show that
this interesting nanoplatform might represent a step forward in the development of innova-
tive and powerful theranostic tools for cancer treatment [217].
5.2.4 Lipid-based micelles
Lipid-based micelles are monolayered spherical structures that self-assemble in aqueous
media, being composed of phospholipids conjugated with PEG. The core contains the acyl
chains and the surface is formed by the polar head groups, being particularly useful for
the encapsulation of hydrophobic compounds [218]. Also, specific targeting moieties may
be grafted on micelles surface [219]. Researchers have developed lipid-based micelles loading
docetaxel, and in vivo noninvasive monitoring was achieved by bioluminescence and fluores-
cence imaging. This nanosystem effectively inhibited tumor growth in a xenograft breast can-
cer model (M2L cells), with no associated toxicity [220]. In a recent work, using biophysical
methods, researchers have characterized oleosin, a hydrophobic protein present in plant
seeds that stabilizes lipid droplets. For this, dodecylphosphocholine micelles were used as
a surrogate platform that mimics lipid droplets, allowing the successful study of oleosin
native structure [221].
5.2.5 Transfersomes
Transfersomes are highly deformable vesicular systems, with a liposomelike structure and
containing surfactants. These are commonly developed for skin appl ications due to their flex-
ibility, facilitating transdermal m ovement [222,223]. Transfersomes loading a-tocopherol, the
most abundant form of vitamin E which is commonly found in vegetable oils (e.g., sunflower,
soybean, and almond), protected skin cells from oxidative damage and enh anced skin wound
closure [224]. In a rat model of arthritis, the topical application of capsaicin-loaded transfer-
somes showed a superior therapeutic activity compared to a commercial antarthritic formu-
lation. Capsaicin is a bioactive principle of Capsicum genus and its association to a delivery
system, besides improving the therapeutic effect, greatly minimized adverse reactions,
such as skin irritation and burning sensation [225]. Also, as a strategy against alopecia, trans-
fersomes coloading caffeine and minoxidil, an approved drug for hair loss treatment, were
designed. In rats, the topical administration of these nanocarriers effectively promoted hair
growth in shaved areas, even compared with commercially available minoxidil hydroalco-
holic solution [226]. Further, in vitro and ex vivo assays were conducted to characterize trans-
fersomes displaying optimized skin permeability of apigenin. The results suggest that this
approach could be used to improve the therapeutic activity of plant-derived compounds
against skin cancer [ 227].
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5.2.6 Ethosomes
Ethosomes are lipid-based vesicles composed of water, phospholipids, and high percent-
age of ethanol (20e50%). Due to their particular composition, ethosomes are highly flexible,
constituting effective tools for topical and transdermal applications [228e230]. Also, ethanol
acts as a permeability enhancer, increasing the fluidity of the lipids present in the stratum cor-
neum [231]. Within the cosmetic field, ethosomes were developed as delivery systems for
loading Geranium essential oil, extracted from Pelargonium graveolens leaves, and Calendula
essential oil, from Calendula officinalis flowers. Globally, the in vitro and in vivo data
confirmed the photoprotective and antiaging activity of these formulations [231]. Caffeic
acid is also known for its photoprotective, anti-inflammatory, and antiaging effects. To mini-
mize chemical instability and to enhance its activity after topical application, caffeic acid was
loaded in ethosomes. Ex vivo assays using porcine skin demonstrated a higher permeation of
caffeic acid and maintenance of its antioxidant properties when associated to ethosomes,
compared to free solution [232]. In an inter esting work focusing on skin cancer ()-epigallo-
catechin-3-O-gallate (EGCG), a natural compound found in tea leaves and green tea, was
exploited as a stabilizing agent of ethosomes. The authors used these EGCG-ethosomes as
nanocarriers of docetaxel to improve its transdermal delivery. In a A375 melanoma murine
model, treatment with this formulation inhibited tumor progression, confirming the thera-
peutic potential against skin cancer [233]. Studies focusing on skin products often compare
formulations using liposomes, transfersomes, and ethosomes. For instance, research on the
topical application of Curcuma longa extracts as photoprotective strategy demonstrated that
transfersomes were the most effective, followed by ethosomes and liposomes [234]. In
another work, topical delivery of a ginsenoside, present in red ginseng, showed that transfer-
somes promoted a significantly higher skin permeation of the bioactive, when compared to
the other two carriers [235].
5.2.7 Phytosomes
These lipid-based vesicles result from the interaction of plant extracts or isolated com-
pounds with phospholipids, mainly phosphatidyl choline [236]. It was in 1989, in Italy,
that these nanosystems were first described, greatly enhancing the bioavailability of polyphe-
nolic extracts [237]. Phytosomes are produced when the polyphenolic moieties establish
hydrogen bonds with the phosphate group of phospholipids, originating a vesicle structure
[236]. Numerous examples of phytosomes containing different plant-derived bioacti ves have
been descri bed in the literature. Phytosomes composed of phosphatidyl choline and piperine,
an alkaloid present in black pepper Piper nigrum [238], were designed. The oral administra-
tion of these domperidone-loaded phytosomes, an anti-emetic drug, enhanced its absorption
and oral bioavailability. Here, piperine acted as bioenhancer, successfully inhibiting the intes-
tinal efflux of domperidone through P-glycoprotein transporter [239]. In respiratory infec-
tions, the use of the polyphenolic compound gingerol, extracted from Zingiber officinale,
could be advantageous [240]. However, it displays aqueous solubility and low stability,
resulting in poor bioavailability. Thus, researchers developed gingerol phytosomes and
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performed in vitro and in vivo studies using Staphylococcus aureus and Escherichia coli. The re-
sults showed anti-inflammatory and antibacterial activities, as well as improved pharmaco-
kinetic and pharmacodynamic profiles [240]. A study to evaluate the potential
chemopreventive effect of curcumin phytosomes on hepatitis B virus (HBV)-related hepato-
carcinogenesis was conducted. When nanoformulated, curcumin exhibited significant anti-in-
flammatory effects and showed higher inhibition of tumor formation, indicating the
chemopreventive potential of this strategy in patients with chronic HBV infection [241].
5.3 Metallic nanoparticles
The interest in medical applications of metallic NPs has increased in recent years, being
considered one of the most promising systems. Resea rch has focused on bioimaging, biosen-
sors, drug delivery, photothermal therapy [242,243], and theranostics [244]. Specifically,
theranostics combine therapeutic and diagnostic modalities, allowing for simultaneous moni-
toring of drug release, drug distribution, and therapeutic efficacy, as well as the location of
the target site [245,246]. For these applications, metallic NPs are relevant since they offer a
large surface area for functionalization. This large surface area allows for metallic NPs to
adsorb a higher number of drug molecules and, thus, increase drug loading [247]. When
compared to drug delivery systems made from other materials, metallic NPs have other pe-
culiarities. For instance, some metallic NPs (i.e., gold NPs) allow for tunability of their phys-
icochemical and optical properties, through the modification of size, morphology, and
surface area [247]. Furthermore, metallic NPs with magnetic properties can be developed.
Upon the application of an external magnetic field, these NPs are directed toward the target
site, constituting an independent strategy from active (i.e., antibodies, ligands) or passive (i.e.,
EPR effect) targeting [248,249].
Usually, metallic NPs are classified regarding their metallic main constituent, and some of
the most researched ones include those composed of gold, silver, titanium dioxide, copper,
magnesium, iron(III) oxide (Fe
2
O
3
), gadolinium oxide (Gd
2
O
3
), and zinc oxide [249e252].
Among these, iron oxide NPs are known fo r their magnetic properties, allowing for both
magnetic targeting and imaging (i.e., Magnetic Resonance Imaging, MRI) [253]; gold NPs
are known for their unique optical properties, being applied for photothermal and photody-
namic therapies, as well as imaging [254e256]; and silver NPs are broadly researched for
their antimicrobial properties, being studied and already implemented in wound healing
and as antimicrobial therapeutics [257]. Importantly, all of the aforementioned NPs have ap-
plications in drug delivery [258e265], with some being involved in the delivery of plant ac-
tives and or derivatives, as presented in Table 3.6.
Metallic NPs are of specific interest in drug delivery due to extremely small sizes
(i.e., <50 nm) that offer a large surface area and, as previously mentioned, resulting in
high drug loadings [285]. These NPs have been described as being able to covalently bind
drugs, such as paclitaxel, to their surface and to deliver the drug to the target [286]. Moreover,
gold NPs are biocompatible and, thus, are not harmful to healthy cells [247,287]. Also, many
metallic NPs are coated with different materials, e.g., polymers, to increase drug conjugation,
5. Nanotechnology as key strategy to deliver bioactives 57
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